α-Keto acids have many uses including the supplementation of amino acids in the treatment of chronic kidney failure (Jungers et al., Blood Purification 1988, 6, 299-314 and Clasen et al., Med. Klin. 1978, 73, 1403-1408).
Conventional methods for the synthesis of α-keto acids have been described in the literature. In one method a Grignard reagent is reacted with a dialkyl oxalate and subsequent hydrolysis of the resulting ester yields the free acid (Rambaud et al., Synthesis 1988, 564 and Macritchie et al., Tetrahedron: Asymmetry 1997, 8, 3895). The acid catalyzed hydrolysis of acyl cyanides affords α-keto acids (Nozaki et al., Tetrahedron: Asymmetry 1993, 4, 2179). Billek reports the preparation of a series of α-keto acids. In this preparation, alkylidenehydantoins are hydrolyzed under basic reaction conditions (Billek, Monath. Chem. 1961, 92, 343-352).
α-Keto acids may be prepared from a corresponding aldehyde by an umpolung reaction. One means of subjecting the aldehyde to umpolung is the formation of a cyclic dithiane, from which a carbanion can be formed by deprotonation with a strong base. This carbanion can subsequently be reacted with carbon dioxide. The cyclic dithiane is finally split under oxidative conditions, for example with mercury salts, to give the desired α-keto acid.

According to studies by Corey and Seebach [Corey et al., Angew. Chem. 1965, 77, 1134-1136 and Seebach et al., J. Org. Chem. 1975, 40, 231-237], dithiols are typically used in order to synthesize cyclic dithioacetals (dithianes). The formation of cyclic five or six membered ring dithianes proceeds preferentially as a result of kinetic preference for cyclization and the high thermodynamic stability of the five- or six-membered ring formed. This high stability, however, is a serious disadvantage, because chemically severe conditions are required to cleave the dithiane ring and release the desired α-keto acid. The cleavage of the dithiane is normally brought about by an oxidation process [Seebach, Synthesis 1969, 17-36]. In this oxidation, the sulfur of the dithiol component being removed is oxidized and then precipitated as a sparingly soluble mercury salt. Therefore, recycle and reuse of the dithiol is not possible. Further disadvantages of this process are the high costs of suitable dithiols, for example, 1,2-ethanedithiol or 1,3-propanedithiol, and the small amounts which would be available for industrial scale use. These problems make the industrial use of the above-described umpolung method very unattractive.
The reaction of short-chain thiols, for example, methyl mercaptan, with aldehydes to give the corresponding thioacetals [Trofimov et al., J. Org. Chem. USSR 1972, 8, 2036 and Rothstein et al., J. Chem. Soc. 1940, 1563] and the use of these dithioacetals in umpolung reactions with various electrophiles is described. However, there is only one literature example of umpolung where the electrophile is CO2 and in that case the thioacetal is aromatic [Micetich et al., Heterocycles 1985, 23, 585-592].
α-Ketomethionine is an α-keto acid of great interest and utility, since it is formed as an intermediate in the organism in the course of conversion of D-methionine to L-methionine.
α-Ketomethionine and its derivatives, for example, its salts or esters, are particularly important compounds, since they constitute alternatives to methionine and to methionine hydroxy analog (MHA) as animal feed additives.
In 1942, Rudolph et al. reported that the sodium salt of α-ketomethionine can be used as a replacement for D,L-methionine, and that it accelerates the growth of young rats (Rudolph et al., J. Biol. Chem. 1942, 145, 210).
It has been shown several times that α-ketomethionine can provide the sulfur required for the biosynthesis of L-methionine and L-cysteine (Sizer et al., Poultry Sci. 1964, 44, 673; Baker et al., Poultry Sci. 1975, 54, 584 and Baker, J. Nutr. 1976, 106, 1376).
In addition, Baker and Harter were able to show that the calcium salt of α-ketomethionine has a relative biological value with regard to the growth of chickens of 83% compared to L-methionine (100%) and MHA (53%) (Baker and Harter, Proceedings of the Society for Experimental Biology and Medicine 1977, 156, 201). The relative biological value of various methionine derivatives, including α-ketomethionine (90% compared to L-methionine), was published by Baker in “Utilization of Precursors for L-Amino Acids” on page 39.
The use of α-ketomethionine and of its salts and esters and amides as an animal feed additive is described in WO 06-72711.
α-Ketomethionine, several salts and other derivatives, such as, for example, ketomethionine esters, are described in the literature. Conventional processes for preparing α-ketomethionine can be divided into chemical and biochemical processes:
a) Biochemical Syntheses:
Meister obtained the sodium salt of α-ketomethionine in a yield of 77% by the oxidation, catalyzed by L-aminooxidases, of methionine (Meister, J. Biol. Chem. 1952, 197, 309). Before that, Waelsch et al., showed that the aminooxidases present in the liver can convert methionine to α-ketomethionine (Waelsch et al., J. Am. Chem. Soc. 1938, 61, 2252).
Mosbach et al. likewise describe the preparation of α-ketomethionine by the oxidation, catalyzed by L-aminooxidases, of methionine. In this preparation, immobilized Providencia sp. PCM 1298 cells are used (Mosbach et al. Enzyme Microb. Technol. 1982, 4, 409).
The disadvantages of the preparation of α-ketomethionine or derivatives thereof with the aid of biological systems, either using purified enzymes or whole cells, are usually the relatively low space-time yields and the technically complicated isolation and product purification. An additional factor in the case of use of high-purity enzymes is that the development, production and purification of the enzymes is very expensive and complicated, and the reuse of already used enzymes is usually not possible.
b) Chemical Syntheses:
In 1957, Sakurai et al. published a first chemical synthesis route for preparing α-ketomethionine. As the key step, methyl α-methoxalyl-γ-methylmercaptopropionate was hydrolyzed with dilute hydrochloric acid to α-ketomethionine (Sakurai et al., J. Biochem. 1957, 44, 9, 557).
Almost at the same time, Yamada et al. published the same synthesis route after first attempts to prepare α-ketomethionine via an α-oximo ester which had been formed as an intermediate afforded only relatively low yields (Chibata et al., Bull. Agr. Chem. Soc. Japan 1957, 21, 336).
The process disclosed by Sakurai and Yamada has the disadvantage that considerable amounts of salt are formed, and therefore, implementation of this process on an industrial scale is not practical. In addition, the synthesis route is not atom-economic, since some of the molecule is eliminated as carbon dioxide in a synthesis step and is thus lost. An industrial scale implementation of this synthesis route would therefore be too expensive, inefficient and environmentally problematic.
Patent application WO 06-72711 describes preparation of α-ketomethionine proceeding from butadiene. In this preparation, butadiene is oxidized selectively to the unsaturated monoepoxide and then converted to the corresponding 1,2-diol by an acid-catalyzed ring opening with water. The subsequent oxidation of the 1,2-diol to the α,β-unsaturated α-keto acid and the subsequent 1,4 addition of MeSH leads to α-ketomethionine.
The high cost of butadiene renders this process unattractive as an industrial scale method to synthesize α-ketomethionine. It is probable that the price of butadiene will again rise significantly in the years to come depending on the price of crude oil. A further disadvantage of the process described in WO 06-727211 is the fact that existing conventional plants for methionine or MHA production could not be used, and therefore, new production plants for every individual process step described would have to be built. The synthesis route described in WO 06-72711 always leads to the free α-ketomethionine, which is unstable and very difficult to isolate.